Informing the pandemic response: the role of the WHO's COVID-19 Weekly Epidemiological Update.

On 31 December 2019, the Municipal Health Commission of Wuhan, China, reported a cluster of atypical pneumonia cases. On 5 January 2020, the WHO publicly released a Disease Outbreak News (DON) report, providing information about the pneumonia cases, implemented response interventions, and WHO's risk assessment and advice on public health and social measures. Following 9 additional DON reports and 209 daily situation reports, on 17 August 2020, WHO published the first edition of the COVID-19 Weekly Epidemiological Update (WEU). On 1 September 2023, the 158th edition of the WEU was published on WHO's website, marking its final issue. Since then, the WEU has been replaced by comprehensive global epidemiological updates on COVID-19 released every 4 weeks. During the span of its publication, the webpage that hosts the WEU and the COVID-19 Operational Updates was accessed annually over 1.4 million times on average, with visits originating from more than 100 countries. This article provides an in-depth analysis of the WEU process, from data collection to publication, focusing on the scope, technical details, main features, underlying methods, impact and limitations. We also discuss WHO's experience in disseminating epidemiological information on the COVID-19 pandemic at the global level and provide recommendations for enhancing collaboration and information sharing to support future health emergency responses.

Evaluation of the cyclic single-chain Fv antibody derived from nivolumab by biophysical analyses and in vitro cell-based bioassay.

Single-chain Fv (scFv) is a recombinant small antibody in which a polypeptide linker connects the variable regions of the light chain (VL) and the heavy chain (VH). The practical use of scFv, however, has been prevented by its tendency to aggregate due to interchain VL-VH interactions. We recently developed a cyclic scFv whose N-terminus and C-terminus were connected by protein ligation techniques. Biophysical comparisons between cyclic and linear scFv have been conducted, but cell biological evaluations remain unexplored. Here we studied the properties of cyclic and linear scFv derived from nivolumab. Biophysical studies revealed that the thermal stability was not changed but that the antigen-binding activity was approximately 3-fold higher as a result of circularization. A cell-based PD-1/PD-L1 interaction inhibitory assay revealed that the biological activity of scFv was markedly higher in the circularized form. In addition, biophysical analysis of scFv proteins incubated in the presence of serum revealed that circularization suppressed the decrease in antigen-binding activity. It could be assumed that circularization of scFv improved stability in the presence of serum, which in turn would suggest the applicability of cyclic scFv as a biopharmaceutical format.

Disseminating information on acute public health events globally: experiences from the WHO's Disease Outbreak News.

WHO works, on a daily basis, with countries globally to detect, prepare for and respond to acute public health events. A vital component of a health response is the dissemination of accurate, reliable and authoritative information. The Disease Outbreak News (DON) reports are a key mechanism through which WHO communicates on acute public health events to the public. The decision to produce a DON report is taken on a case-by-case basis after evaluating key criteria, and the subsequent process of producing a DON report is highly standardised to ensure the robustness of information. DON reports have been published since 1996, and up to 2022 over 3000 reports have been published. Between 2018 and 2022, the most frequently published DON reports relate to Ebola virus disease, Middle East respiratory syndrome, yellow fever, polio and cholera. The DON web page is highly visited with a readership of over 2.6 million visits per year, on average. The DON report structure has evolved over time, from a single paragraph in 1996 to a detailed report with seven sections currently. WHO regularly reviews the DON report process and structure for improvements. In the last 25 years, DON reports have played a unique role in rapidly disseminating information on acute public health events to health actors and the public globally. They have become a key information source for the global public health response to the benefit of individuals and communities.

Health Emergency Risk Management in World Health Organization - South-East Asia Region during 2014-2023: synthesis of experiences.

Health Emergency Risk Management (ERM) has become increasingly critical on the global stage, prompted by the escalating frequency and severity of natural disasters and disease outbreaks. This paper offers a comprehensive synthesis of the World Health Organization's (WHO) experiences in the South-East Asia Region during the period 2014-2023, shedding light on its efforts to manage health emergencies and enhance resilience. The South-East Asia Region's unique environmental and economic diversity exposes it to significant health risks, including emerging infectious diseases and their implications for development, particularly in low-income countries. Here we document the transition from reactive emergency responses to proactive preparedness, catalyzed by prioritizing ERM as one of the regional flagship priorities in 2014. Key components of this initiative included capacity-building, the establishment of the South-East Asia Regional Health Emergency Fund (SEARHEF), and the implementation of the International Health Regulations (IHR 2005). This synthesis highlights the region's achievements in event reporting, development of national actions plan, successful Early Warning, Alert, and Response System (EWARS) implementation, and improvements in core capacities under IHR (2005). It also underscores the challenges associated with cross-border data sharing and regional collaboration that could strengthen ERM and enhance readiness for effective synergistic response.

Surveillance for variants of SARS-CoV-2 to inform risk assessments.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged, some leading to large increases in infections, hospitalizations and deaths globally. The virus's impact on public health depends on many factors, including the emergence of new viral variants and their global spread. Consequently, the early detection and surveillance of variants and characterization of their clinical effects are vital for assessing their health risk. The unprecedented capacity for viral genomic sequencing and data sharing built globally during the pandemic has enabled new variants to be rapidly detected and assessed. This article describes the main variants circulating globally between January 2020 and June 2023, the genetic features driving variant evolution, and the epidemiological impact of these variants across countries and regions. Second, we report how integrating genetic variant surveillance with epidemiological data and event-based surveillance, through a network of World Health Organization partners, supported risk assessment and helped provide guidance on pandemic responses. In addition, given the evolutionary characteristics of circulating variants and the immune status of populations, we propose future directions for the sustainable genomic surveillance of SARS-CoV-2 variants, both nationally and internationally: (i) optimizing variant surveillance by including environmental monitoring; (ii) coordinating laboratory assessment of variant evolution and phenotype; (iii) linking data on circulating variants with clinical data; and (iv) expanding genomic surveillance to additional pathogens. Experience during the COVID-19 pandemic has shown that genomic surveillance of pathogens can provide essential, timely and evidence-based information for public health decision-making.

Depuis le début de la pandémie de coronavirus survenue en 2019 (COVID-19), de nombreux variants du coronavirus 2 du syndrome respiratoire aigu sévère (SARS-CoV-2) sont apparus, certains entraînant une forte augmentation du nombre d'infections, d'hospitalisations et de décès dans le monde. L'impact du virus sur la santé publique dépend de nombreux facteurs, notamment l'émergence de nouveaux variants viraux et leur propagation à l'échelle mondiale. Par conséquent, la détection précoce et la surveillance des variants ainsi que la caractérisation de leurs effets cliniques sont essentielles pour évaluer leur risque pour la santé. La capacité sans précédent de séquençage du génome viral et de partage des données, capacité mise en place à l'échelle mondiale pendant la pandémie, a permis de détecter et d'évaluer rapidement de nouveaux variants. Le présent article décrit les principaux variants circulant dans le monde entre janvier 2020 et juin 2023, les caractéristiques génétiques à l'origine de leur évolution et leur impact épidémiologique dans les différents pays et régions. Ensuite, nous expliquerons comment l'intégration de la surveillance des variants génétiques aux données épidémiologiques et à la surveillance fondée sur les événements, par l'intermédiaire d'un réseau de partenaires de l'Organisation mondiale de la santé, a permis de faciliter l'évaluation des risques et de fournir des orientations sur les mesures à prendre en période de pandémie. En outre, compte tenu des caractéristiques évolutives des variants en circulation et de l'état immunitaire des populations, nous proposons des orientations futures pour une surveillance génomique durable des variants du SARS-CoV-2, au niveau tant national qu'international: (i) optimiser la surveillance des variants en incluant le suivi environnemental; (ii) coordonner l'évaluation en laboratoire de l'évolution des variants et du phénotype; (iii) établir un lien entre les données sur les variants en circulation et les données cliniques; et (iv) étendre la surveillance génomique à d'autres agents pathogènes. L'expérience de la pandémie de COVID-19 a mis en évidence que la surveillance génomique des agents pathogènes peut fournir en temps utile des informations essentielles fondées sur des preuves en vue de la prise de décisions en matière de santé publique.

Desde el inicio de la pandemia de la enfermedad por coronavirus de 2019 (COVID-19), han aparecido numerosas variantes del coronavirus de tipo 2 causante del síndrome respiratorio agudo severo (SRAS-CoV-2), algunas de las que han provocado un gran aumento de las infecciones, hospitalizaciones y muertes en todo el mundo. El impacto del virus en la salud pública depende de muchos factores, entre ellos la aparición de nuevas variantes víricas y su propagación mundial. En consecuencia, la detección y vigilancia tempranas de las variantes y la caracterización de sus efectos clínicos son vitales para evaluar su riesgo sanitario. La capacidad sin precedentes de secuenciación genómica viral y de intercambio de datos creada a nivel mundial durante la pandemia ha permitido detectar y evaluar rápidamente variantes nuevas. En este artículo se describen las principales variantes que circulan a nivel mundial entre enero de 2020 y junio de 2023, la característica genética que impulsa la evolución de las variantes y el impacto epidemiológico de estas variantes en los diferentes países y regiones. En segundo lugar, se informa de cómo la integración de la vigilancia de variantes genéticas con los datos epidemiológicos y la vigilancia basada en eventos, a través de una red de asociados de la Organización Mundial de la Salud, apoyó la evaluación de riesgos y ayudó a proporcionar orientación sobre las respuestas a la pandemia. Además, dadas las características evolutivas de las variantes circulantes y el estado inmunitario de las poblaciones, se proponen orientaciones futuras para la vigilancia genómica sostenible de las variantes del SRAS-CoV-2, tanto a nivel nacional como internacional: (i) optimizar la vigilancia de las variantes mediante la inclusión de la monitorización ambiental; (ii) coordinar la evaluación de laboratorio de la evolución y el fenotipo de las variantes; (iii) vincular los datos sobre las variantes circulantes con los datos clínicos; y (iv) ampliar la vigilancia genómica a patógenos adicionales. La experiencia durante la pandemia de la COVID-19 ha demostrado que la vigilancia genómica de patógenos puede proporcionar información esencial, oportuna y basada en evidencias para la toma de decisiones en materia de salud pública.

A global research agenda on public health and social measures during emergencies.

The importance of strong coordination for research on public health and social measures was highlighted at the Seventy-fourth World Health Assembly in 2021. This article describes efforts undertaken by the World Health Organization (WHO) to develop a global research agenda on the use of public health and social measures during health emergencies. This work includes a multistep process that started with a global technical consultation convened by WHO in September 2021. The consultation included experts from around the world and from a wide range of disciplines, such as public health, education, tourism, finance and social sciences, and aimed to identify research and implementation approaches based on lessons learnt during the coronavirus disease 2019 pandemic. To prepare for future epidemics and pandemics, it is essential to adopt a more robust, comparable and systematic research approach to public health and social measures. Such comprehensive approach will better inform agile, balanced and context-specific implementation decisions during future emergencies. This article describes the methods used to develop global research priorities for public health and social measures and the next steps needed.

La soixante-quatorzième Assemblée mondiale de la Santé en 2021 a souligné l'importance d'une coordination solide pour la recherche sur la santé publique et les mesures sociales. Le présent article décrit les efforts entrepris par l'Organisation mondiale de la santé (OMS) pour élaborer un programme de recherche mondial sur l'utilisation des mesures de santé publique et des mesures sociales lors de situations d'urgence sanitaire. Ce travail comprend un processus en plusieurs étapes qui a commencé par une consultation technique mondiale organisée par l'OMS en septembre 2021. La consultation a réuni des experts du monde entier issus d'un large éventail de disciplines telles que la santé publique, l'éducation, le tourisme, la finance et les sciences sociales. Elle visait à identifier des approches de recherche et de mise en œuvre fondées sur les enseignements tirés de la pandémie de maladie à coronavirus de 2019. Pour se préparer aux futures épidémies et pandémies, il est essentiel d'adopter une approche de recherche plus solide, comparable et systématique en matière de santé publique et de mesures sociales. Cette approche globale permettra de mieux éclairer les décisions de mise en œuvre agiles, équilibrées et adaptées au contexte lors des futures situations d'urgence. Le présent article décrit les méthodes appliquées pour définir les priorités mondiales de recherche en matière de santé publique et de mesures sociales, ainsi que les prochaines étapes à franchir.

En la 74.ª Asamblea Mundial de la Salud, celebrada en 2021, se destacó la importancia de una sólida coordinación en la investigación sobre salud pública y medidas sociales. Este artículo describe los esfuerzos que ha emprendido la Organización Mundial de la Salud (OMS) para desarrollar un programa mundial de investigación sobre el uso de medidas sociales y de salud pública durante las emergencias sanitarias. Este trabajo incluye un proceso de varios pasos que comenzó con una consulta técnica mundial que convocó la OMS en septiembre de 2021. La consulta incluyó a expertos de todo el mundo y de una gran variedad de disciplinas, como la salud pública, la educación, el turismo, las finanzas y las ciencias sociales, y tuvo como objetivo identificar enfoques de investigación y aplicación basados en las lecciones aprendidas durante la pandemia de la enfermedad por coronavirus de 2019. Para prepararse ante futuras epidemias y pandemias, es esencial adoptar un enfoque de investigación más sólido, comparable y sistemático en materia de salud pública y medidas sociales. Este enfoque integral informará mejor las decisiones de aplicación ágiles, equilibradas y adaptadas al contexto durante futuras emergencias. En este artículo se describen los métodos utilizados para elaborar las prioridades mundiales de investigación sobre salud pública y medidas sociales, así como los próximos pasos necesarios.

Natural history of eosinophil­derived neurotoxin levels and the onset of allergic airway disease in preschool children.

'Atopic march' is the progression of allergic conditions through infancy and childhood. The present study investigated the association between blood eosinophil-derived neurotoxin (EDN) levels in preschool children with food allergy (FA) or atopic dermatitis (AD) and the onset of allergic airway disease [bronchial asthma (BA), allergic rhinitis (AR)]. A total of 123 children below the age of 1 year were enrolled in the present study, along with controls (n=37). Blood specimens were taken, serum EDN levels were measured and immunoglobulin E was quantified. Finally, a total of 86 subjects were analyzed. EDN values were measured at 3 time-points: before 1 year of age, before 2 years of age and before 3 years of age. The EDN levels were initially similar between those patients who did and those who did not develop allergic airway disease but then markedly diverged at the 2-year time-point (226.6 vs. 65.0 ng/ml; P<0.01) and remained divergent at the 3-year time-point (173.9 vs. 62.7 ng/ml; P<0.01). EDN levels prior to diagnosis were compared between the two groups and they were much higher in the Onset group (n=10) compared to the Non-onset group (n=67) (171.2±34.28 vs. 81.3±10.02 ng/ml; P=0.003), with 4 cases of BA and 6 cases of AR in the Onset group. After diagnosis, EDN levels were compared twice: i) At 1 and 2 years of age; and ii) 1 and 3 years of age. A significant difference was found only in the comparison at 2 years (P=0.001). In conclusion, young children with elevated EDN levels during the FA/AD disease period were more likely to develop allergic airway disease (BA, AR) in their first three years of life. A factor leading to this progression may be increased eosinophil activity.

Global public health intelligence: World Health Organization operational practices.

Early warning and response are key to tackle emerging and acute public health risks globally. Therefore, the World Health Organization (WHO) has implemented a robust approach to public health intelligence (PHI) for the global detection, verification and risk assessment of acute public health threats. WHO's PHI operations are underpinned by the International Health Regulations (2005), which require that countries strengthen surveillance efforts, and assess, notify and verify events that may constitute a public health emergency of international concern (PHEIC). PHI activities at WHO are conducted systematically at WHO's headquarters and all six regional offices continuously, throughout every day of the year. We describe four interlinked steps; detection, verification, risk assessment, and reporting and dissemination. For PHI operations, a diverse and interdisciplinary workforce is needed. Overall, PHI is a key feature of the global health architecture and will only become more prominent as the world faces increasing public health threats.

Mpox in Children and Adolescents during Multicountry Outbreak, 2022-2023.

The 2022-2023 mpox outbreak predominantly affected adult men; 1.3% of reported cases were in children and adolescents <18 years of age. Analysis of global surveillance data showed 1 hospital intensive care unit admission and 0 deaths in that age group. Transmission routes and clinical manifestations varied across age subgroups.

Usefulness of aMAP Risk Score for Predicting Recurrence after Curative Treatment for Hepatocellular Carcinoma within Milan Criteria.

INTRODUCTION: The aMAP score is a prediction model for hepatocellular carcinoma (HCC) risk in chronic hepatitis patients. This study was conducted to elucidate the utility of this model for predicting initial recurrence of HCC in patients within the Milan criteria after undergoing curative treatment. METHODS: Patients with naïve HCC within the Milan criteria (n = 1,020) and treated from January 2000 to August 2022 were enrolled. The cohort was divided into two groups according to the aMAP score (high ≥60, low <60) and then compared for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Comparisons between the high and low groups showed that etiology (HBV:HCV:HBV+HCV:NBNC = 41:79:2:37 vs. 65:589:11:196, p < 0.001), AST (36 vs. 46 IU/L, p < 0.001), and multiple HCC occurrence (15% vs. 22%, p = 0.026) were significantly different. Additionally, median RFS (59.8 vs. 30.9 months; p < 0.001) and median OS (154.1 vs. 83.4 months, p < 0.01) were greater in the low group. As for patients with HCC due to chronic viral hepatitis, there was a significant difference in median RFS between the groups (59.8 vs. 30.6 months, p < 0.001), especially for HCV-positive patients (53.1 vs. 27.2 months, p = 0.002). In patients with HCC due to a nonviral cause, the difference in median RFS between the low (70.9 months) and high (32.0 months) groups was not significant. DISCUSSION: Findings of this retrospective study indicate a significant association of elevated aMAP with worse RFS in patients with HCC caused by chronic viral hepatitis, especially those with HCV. The aMAP score is considered useful to predict not only HCC-carcinogenesis risk but also risk of recurrence following curative treatment.

WHO Global Situational Alert System: a mixed methods multistage approach to identify country-level COVID-19 alerts.

BACKGROUND: Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly basis in 237 countries, territories and areas from May 2021 to June 2022. This aimed to facilitate the early identification of situations where healthcare capacity may become overstretched. METHODS: The process involved a three-stage mixed methods approach. In the first stage, future deaths were predicted from the time series of reported cases and deaths to produce an initial alert level. In the second stage, this alert level was adjusted by incorporating a range of contextual indicators and accounting for the quality of information available using a Bayes classifier. In the third stage, countries with an alert level of 'High' or above were added to an operational watchlist and assistance was deployed as needed. RESULTS: Since June 2021, the system has supported the release of more than US$27 million from WHO emergency funding, over 450 000 rapid antigen diagnostic testing kits and over 6000 oxygen concentrators. Retrospective evaluation indicated that the first two stages were needed to maximise sensitivity, where 44% (IQR 29%-67%) of weekly watchlist alerts would not have been identified using only reported cases and deaths. The alerts were timely and valid in most cases; however, this could only be assessed on a non-representative sample of countries with hospitalisation data available. CONCLUSIONS: The system provided a standardised approach to monitor the pandemic at the country level by incorporating all available data on epidemiological analytics and contextual assessments. While this system was developed for COVID-19, a similar system could be used for future outbreaks and emergencies, with necessary adjustments to parameters and indicators.

Strengthening pathogen genomic surveillance for health emergencies: insights from the World Health Organization's regional initiatives.

The onset of the COVID-19 pandemic triggered a rapid scale-up in the use of genomic surveillance as a pandemic preparedness and response tool. As a result, the number of countries with in-country SARS-CoV-2 genomic sequencing capability increased by 40% from February 2021 to July 2022. The Global Genomic Surveillance Strategy for Pathogens with Pandemic and Epidemic Potential 2022-2032 was launched by the World Health Organization (WHO) in March 2022 to bring greater coherence to ongoing work to strengthen genomic surveillance. This paper describes how WHO's tailored regional approaches contribute to expanding and further institutionalizing the use of genomic surveillance to guide pandemic preparedness and response measures as part of a harmonized global undertaking. Challenges to achieving this vision include difficulties obtaining sequencing equipment and supplies, shortages of skilled staff, and obstacles to maximizing the utility of genomic data to inform risk assessment and public health action. WHO is helping to overcome these challenges in collaboration with partners. Through its global headquarters, six regional offices, and 153 country offices, WHO is providing support for country-driven efforts to strengthen genomic surveillance in its 194 Member States, with activities reflecting regional specificities. WHO's regional offices serve as platforms for those countries in their respective regions to share resources and knowledge, engage stakeholders in ways that reflect national and regional priorities, and develop regionally aligned approaches to implementing and sustaining genomic surveillance within public health systems.

Description of the first global outbreak of mpox: an analysis of global surveillance data.

BACKGROUND: In May 2022, several countries with no history of sustained community transmission of mpox (formerly known as monkeypox) notified WHO of new mpox cases. These cases were soon followed by a large-scale outbreak, which unfolded across the world, driven by local, in-country transmission within previously unaffected countries. On July 23, 2022, WHO declared the outbreak a Public Health Emergency of International Concern. Here, we aim to describe the main epidemiological features of this outbreak, the largest reported to date. METHODS: In this analysis of global surveillance data we analysed data for all confirmed mpox cases reported by WHO Member States through the global surveillance system from Jan 1, 2022, to Jan 29, 2023. Data included daily aggregated numbers of mpox cases by country and a case reporting form (CRF) containing information on demographics, clinical presentation, epidemiological exposure factors, and laboratory testing. We used the data to (1) describe the key epidemiological and clinical features of cases; (2) analyse risk factors for hospitalisation (by multivariable mixed-effects binary logistic regression); and (3) retrospectively analyse transmission trends. Sequencing data from GISAID and GenBank were used to analyse monkeypox virus (MPXV) genetic diversity. FINDINGS: Data from 82 807 cases with submitted CRFs were included in the analysis. Cases were primarily due to clade IIb MPXV (mainly lineage B.1, followed by lineage A.2). The outbreak was driven by transmission among males (73 560 [96·4%] of 76 293 cases) who self-identify as men who have sex with men (25 938 [86·9%] of 29 854 cases). The most common reported route of transmission was sexual contact (14 941 [68·7%] of 21 749). 3927 (7·3%) of 54 117 cases were hospitalised, with increased odds for those aged younger than 5 years (adjusted odds ratio 2·12 [95% CI 1·32-3·40], p=0·0020), aged 65 years and older (1·54 [1·05-2·25], p=0·026), female cases (1·61 [1·35-1·91], p<0·0001), and for cases who are immunosuppressed either due to being HIV positive and immunosuppressed (2·00 [1·68-2·37], p<0·0001), or other immunocompromising conditions (3·47 [1·84-6·54], p=0·0001). INTERPRETATION: Continued global surveillance allowed WHO to monitor the epidemic, identify risk factors, and inform the public health response. The outbreak can be attributed to clade IIb MPXV spread by newly described modes of transmission. FUNDING: WHO Contingency Fund for Emergencies. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Food protein-induced enterocolitis syndrome due to buckwheat: A case report.

Buckwheat is a rare causative food for food protein-induced enterocolitis syndrome (FPIES). To date, it is unknown what laboratory data patients with FPIES caused by buckwheat show. We report a 4-year-old female with FPIES caused by buckwheat and the laboratory results. Skin prick, specific IgE antibody, and basophil activation tests were negative; however, the lymphocyte stimulation test (LST) revealed a 10.2-fold increase in activation compared with the negative control. In an open-label oral food challenge (OFC) of 80 g boiled buckwheat noodles, 3 hours after ingestion, vomiting occurred four times in a 2-hour duration. Therefore, we diagnosed the patient with FPIES caused by buckwheat. Her neutrophil count, C-reactive protein, and thymus and activation-regulated chemokine were elevated after the OFC. Moreover, the patient had a positive reaction to the LST, which may theoretically be useful in diagnosing non-immunoglobulin E-mediated gastrointestinal food allergies. FPIES caused by buckwheat is rare; however, we found that the same laboratory results were observed in a comparison of FPIES cases caused by other foods.

Molecular characterization of a flavanone 3-hydroxylase gene from citrus fruit reveals its crucial roles in anthocyanin accumulation.

BACKGROUND: Flavanone 3-hydroxylase (F3H), a key enzyme in the flavonoid biosynthetic pathway, plays an important role in the regulation of flavonols and anthocyanidins accumulation. Citrus fruit is a rich source of flavonoids with varied flavonoid compositions among different varieties. To date, the study on F3H is limited in citrus, and its roles in regulating flavonoid accumulation in citrus fruit are still unclear. RESULTS: In this study, we isolated a CitF3H from three different citrus varieties, Satsuma mandarin (Citrus unshiu Marc.), Ponkan mandarin (C. reticulata Blanco) and blood orange 'Moro' (C. sinensis Osbeck). Functional analysis showed that CitF3H encoded a functional flavanone 3-hydroxylase. It catalyzed the hydroxylation of naringenin to yield dihydrokaempferol, which was a precursor of anthocyanins in flavonoid biosynthetic pathway. In the juice sacs, CitF3H was differentially expressed among the three citrus varieties, and its expression level was positively correlated with the accumulation of anthocyanins during the ripening process. In the juice sacs of Satsuma mandarin and Ponkan mandarin the expression of CitF3H kept constant at an extremely low level, and no anthocyanin was accumulated during the ripening process. In contrast, the expression of CitF3H increased rapidly along with the accumulation of anthocyanin in the juice sacs of blood orange 'Moro' during the ripening process. In addition, we found that blue light irradiation was effective to up-regulate the expression of CitF3H and improve anthocyanin accumulation in the juice sacs of blood orange 'Moro' in vitro. CONCLUSION: CitF3H was a key gene regulating anthocyanin accumulation in the juice sacs of citrus fruit. The results presented in this study will contribute to elucidating anthocyanin biosynthesis in citrus fruit, and provide new strategies to improve the nutritional and commercial values of citrus fruit.

Food protein-induced enterocolitis syndrome due to buckwheat: A case report

Buckwheat is a rare causative food for food protein–induced enterocolitis syndrome (FPIES). To date, it is unknown what laboratory data patients with FPIES caused by buckwheat show. We report a 4-year-old female with FPIES caused by buckwheat and the laboratory results. Skin prick, specific IgE antibody, and basophil activation tests were negative; however, the lymphocyte stimulation test (LST) revealed a 10.2-fold increase in activation compared with the negative control. In an open-label oral food challenge (OFC) of 80 g boiled buckwheat noodles, 3 hours after ingestion, vomiting occurred four times in a 2-hour duration. Therefore, we diagnosed the patient with FPIES caused by buckwheat. Her neutrophil count, C-reactive protein, and thymus and activation-regulated chemokine were elevated after the OFC. Moreover, the patient had a positive reaction to the LST, which may theoretically be useful in diagnosing non-immunoglobulin E-mediated gastrointestinal food allergies. FPIES caused by buckwheat is rare; however, we found that the same laboratory results were observed in a comparison of FPIES cases caused by other foods (AU)